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Biochem Pharmacol. 2017 Apr 15;130:71-82. doi: 10.1016/j.bcp.2017.02.004. Epub 2017 Feb 9.

Selective upregulation of TNFα expression in classically-activated human monocyte-derived macrophages (M1) through pharmacological interference with V-ATPase.

Author information

1
Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany. Electronic address: lea.thomas@uni-jena.de.
2
Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany. Electronic address: zhigang.rao@uni-jena.de.
3
Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany. Electronic address: jana.gerstmeier@uni-jena.de.
4
Institute of Biochemistry II and Center for Sepsis Control and Care, University Hospital Jena, Jena, Germany. Electronic address: Martin.Raasch@med.uni-jena.de.
5
Institute of Transfusion Medicine, University Hospital Jena, Jena, Germany. Electronic address: christina.weinigel@med.uni-jena.de.
6
Institute of Transfusion Medicine, University Hospital Jena, Jena, Germany. Electronic address: silke.rummler@med.uni-jena.de.
7
Kekulé-Institut für Organische Chemie und Biochemie der Rheinischen Friedrich-Wilhelms-Universität Bonn, Bonn, Germany. Electronic address: dirk.menche@uni-bonn.de.
8
Helmholtz-Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology at Saarland University, Germany. Electronic address: Rolf.Mueller@helmholtz-hzi.de.
9
Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany. Electronic address: pergolacarlo@googlemail.com.
10
Institute of Biochemistry II and Center for Sepsis Control and Care, University Hospital Jena, Jena, Germany. Electronic address: Alexander.MOSIG@med.uni-jena.de.
11
Institute of Pharmacy, Friedrich Schiller University Jena, Philosophenweg 14, D-7743 Jena, Germany. Electronic address: oliver.werz@uni-jena.de.

Abstract

Pharmacological interference with vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, is considered a potential strategy for cancer therapy. Macrophages are critically involved in tumor progression and may occur as pro-tumoral M2 phenotype, whereas classically-activated M1 can inhibit tumor development for example by releasing tumor-suppressing molecules, including tumor necrosis factor (TNF)α. Here, we show that targeting V-ATPase by selective inhibitors such as archazolid upregulates the expression and secretion of TNFα in lipopolysaccharide (LPS)- or LPS/interferon (INF)γ-activated M1-like macrophages derived from human blood monocytes. In contrast, archazolid failed to elevate TNFα production from uncommitted (M0) or interleukin (IL)-4-treated M2-like macrophages. Secretion of other relevant cytokines (i.e., IL-1β, IL-6, IL-10) or chemokines (i.e. IL-8 and monocyte chemotactic protein-1) from M1 was not affected by archazolid. Though V-ATPase inhibitors elevated the lysosomal pH in M1 comparable to chloroquine or ammonium chloride, the latter agents suppressed TNFα secretion. Archazolid selectively increased TNFα mRNA levels, which was abolished by dexamethasone. Interestingly, archazolid enhanced the phosphorylation and nuclear translocation of the p65 subunit of NFκB and stimulated phosphorylation of SAPK/JNK. In a microfluidically-supported human tumor biochip model, archazolid-treated M1 significantly reduced tumor cell viability. Together, our data show that V-ATPase inhibition selectively upregulates TNFα production in classically-activated macrophages along with NFκB and SAPK/JNK activation. Such increased TNFα release caused by V-ATPase inhibitors may contribute to tumor suppression in addition to direct targeting cancer cells.

KEYWORDS:

Archazolid; Interleukin; Macrophages; NFκB; Tumor necrosis factor α; Vacuolar-type H(+)-ATPase

PMID:
28189727
DOI:
10.1016/j.bcp.2017.02.004
[Indexed for MEDLINE]

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